Alpha-mangostin inhibits dengue virus production and pro-inflammatory cytokine/chemokine expression in dendritic cells

Dengue virus (DENV) is transmitted to humans via the bite of an Aedes mosquito, causing dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. In the human skin, DENV first infects keratinocytes, dendritic cells, and macrophages. Monocytes that are recruited to the site of infection and differentiate into monocyte-derived dendritic cells (moDCs) are also infected by DENV. DENV-infected DCs secrete pro-inflammatory cytokines and chemokines to modulate the immune response. The viral load and massive pro-inflammatory cytokine/chemokine production, referred to as a 'cytokine storm', are associated with disease severity. We propose that an ideal drug for treatment of DENV infection should inhibit both virus production and the cytokine storm, and previously, we reported that alpha-mangostin (alpha-MG) inhibits both DENV replication and cytokine production in hepatocytes. However, the effect of alpha-MG on DENV-infected moDCs remains unknown. In this study, we investigated the effects of alpha-MG on DENV infection and pro-inflammatory cytokine/chemokine production in primary moDCs generated ex vivo from monocytes of healthy individuals. alpha-MG at the non-toxic concentrations of 20 and 25 mu M reduced DENV production by more than 10-fold and 1,000-fold, respectively. Treatment with alpha-MG efficiently inhibited the infection of immature moDCs by all four serotypes of DENV. Time-of-addition studies suggested that alpha-MG (25 mu M) inhibits DENV at the early stage of replication. In addition, alpha-MG markedly reduced cytokine/chemokine (TNF-alpha, CCL4, CCL5, CXCL10, IL6, IL1 beta, IL10, and IFN-alpha) transcription in DENV-infected immature moDCs. These findings suggest the potential of alpha-MG to be developed as a novel anti-DENV drug.

Automated summary

Dengue virus is transmitted by Aedes mosquitoes and infects various types of cells in the human skin, leading to diseases like dengue fever. Inhibiting virus production and the cytokine storm is critical for effective treatment of DENV infection.